DESCRIPTION (author's): We propose to investigate why central visual pathways fail to regenerate after injury and how their repair can be enhanced. We will focus on the mechanisms that normally control the survival and growth of retinal ganglion cells (RGCs) and their axons, as well as the properties of adult oligodendrocyte precursor cells, the suspected source of new oligodendrocytes after injury. The rat optic nerve, which consists mainly of retinal ganglion cell axons and myelinating oligodendreocytes, will be used as a model system. The survival of RGCs and their axons is normally controlled by peptide signals, such as brain-derived neurotrophic factor (BDNF), that are released by neighboring cells--tectal target neurons, optic nerve astrocytes and oligodendrocytes--and retrogradely transported to the cell soma. When RGC axons are cut, their axons degenerate and the RGCs themselves subsequently die, presumably because they fail to get needed survival signals. In addition, we have recently found that electrical activity of RGCs, which may be diminished after injury, is necessary for their responsiveness to these factors. These findings raise a question, do RGC axons fail to regenerate after injury primarily because RGCs fail to survive? To test this hypothesis, we will first further characterize the signaling mechanisms that normally promote RGC survival. We have previously developed methods to purify and culture rat RGCs and found that the purified RGCs rapidly undergo programmed cell death in the absence of survival-promoting signals from their normal neighboring cell types. Several of these survival signals have already been elucidated and our preliminary results provide clear evidence for two new survival signals for RGCs produced by optic rectum and oligodendrocytes. We propose to further characterize and clone these signals. Secondly, we have found that electrically active RGCs are more responsive to their trophic factors and that this effect can be mimicked by increasing their intracellular levels of cAMP. We will investigate how electrical activity enhances the ability of RGCs to respond to their peptide trophic factors. Our ultimate goal is to determine whether in vivo delivery of RGC survival factors together with substances that mimic electrical activity will promote axonal regeneration after injury.